We have previously reported that prior administration of interleukin 1 (IL 1) or tumor necrosis factor (TNF) protects mice from lethal doses of irradiation. G-CSF, GM-CSF, IL 2 or interferon alpha, beta (IFN alpha, beta) prevent the lethal effect of less than 900 r dose of irradiation whereas IL 1 and TNF synergized as radioprotectors. Pretreatment with G-CSF or GM-CSF together with suboptimal doses of IL 1 also had synergistic radioprotective effects. The radioprotective effect of cytokines is associated with stimulation of bone marrow (BM) hematopoietic cells: 1) The recovery of nucleated BM cells and of hematopoietic progenitor cells were enhanced in IL 1 pretreated lethally irradiated mice. 2) In vivo treatment of normal mice with IL 1, for 24 hrs results in BM cell enlargement, increased cell cycling and increased capacity to proliferate in vitro in response to GM- CSF. We are currently showing positive effects of IL 1 treatment on isologous as well as allogeneic BM transplants. Isologous BM cells synergize with IL 1 to protect mice against supralethal doses (1500 r) of irradiation. IL 1 also enhances the survival of irradiated mice given low numbers of allogeneic BM cells. We are also evaluating the therapeutic effects of cytokine administration following midlethal doses of radiation. We have preliminary results suggesting that IL 1, IFN-gamma and TNF, but neither G-CSF nor GM-CSF significantly improve survival if given immediately after irradiation. Studies of the mechanism of radioprotection by IL 1 revealed that IL 1, in a variety of target cells, rapidly induces a p25 moiety which was purified to homogeneity and identified as mitochondrial manganese superoxide dismutase (MnSOD). However, IL 1 failed to induce other intracellular scavengers such as glutathione peroxidase and catalase. It is possible that MnSOD contributes to the radioprotective effects of IL 1.